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Objective: Mitochondria‐associated membranes (MAMs) serve pivotal functions in hepatic insulin resistance (IR). Our aim was to explore the potential role of MAMs in mitigating hepatic IR through exercise and to compare the effects of different intensities of exercise on hepatic MAMs formation in high‐fat diet (HFD) mice. Methods: Male C57BL/6J mice were fed an HFD and randomly assigned to undergo supervised high‐intensity interval training (HIIT) or moderate‐intensity continuous training (MICT). IR was evaluated using the serum triglyceride/high‐density lipoprotein cholesterol ratio (TG/HDL‐C), glucose tolerance test (GTT), and insulin tolerance test (ITT). Hepatic steatosis was observed using hematoxylin–eosin (H&E) and oil red O staining. The phosphatidylinositol 3‐kinase/protein kinase B/glycogen synthase kinase 3 beta (PI3K‐AKT‐GSK3β) signaling pathway was assessed to determine hepatic IR. MAMs were evaluated through immunofluorescence (colocalization of voltage‐dependent anion‐selective channel 1 [VDAC1] and inositol 1,4,5‐triphosphate receptor [IP3R]). Results: After 8 weeks on an HFD, there was notable inhibition of the hepatic PI3K/Akt/GSK3β signaling pathway, accompanied by a marked reduction in hepatic IP3R‐VDAC1 colocalization levels. Both 8‐week HIIT and MICT significantly enhanced the hepatic PI3K/Akt/GSK3β signaling and colocalization levels of IP3R‐VDAC1 in HFD mice, with MICT exhibiting a stronger effect on hepatic MAMs formation. Furthermore, the colocalization of hepatic IP3R‐VDAC1 positively correlated with the expression levels of phosphorylation of protein kinase B (p‐AKT) and phosphorylation of glycogen synthase kinase 3 beta (p‐GSK3β), while displaying a negative correlation with serum triglyceride/high‐density lipoprotein cholesterol levels. Conclusion: The reduction in hepatic MAMs formation induced by HFD correlates with the development of hepatic IR. Both HIIT and MICT effectively bolster hepatic MAMs formation in HFD mice, with MICT demonstrating superior efficacy. Thus, MAMs might wield a pivotal role in exercise‐induced alleviation of hepatic IR. [ABSTRACT FROM AUTHOR]

Bismuth ferrite (BiFeO3) possesses a non‐collinear spin order while the ferroelectric order breaks space inversion symmetry. This allows efficient electric‐field control of magnetism and makes it a promising candidate for applications in low‐power spintronic devices. Epitaxial strain effects have been intensively studied and exhibit significant modulation of the magnetic order in bismuthBiFeO3, but tuning its spin structure with continuously varied uniaxial strain is still lacking at this moment. Herein, in situ uniaxial tensile strain is applied to a freestanding BiFeO3 film by mechanically stretching an organic substrate. A scanning nitrogen‐vacancy (NV) microscopy is applied to image the nanoscale magnetic order in real space. The strain is continuously increased from 0% to 1.5% and four images under different strains are acquired during this period. The images show that the spin cycloid tilts by ≈12.6° when strain approaches 1.5%. A first principle calculation is processed to show that the tilting is energetically favorable under such strain. The in situ strain applying method in combination with scanning NV microscope real‐space imaging ability paves a new way in studying the coupling between magnetic order and strain in BiFeO3 films. [ABSTRACT FROM AUTHOR]

The zoonotic Lyme neuroborreliosis (LNB) disease is caused by Borrelia burgdorferi, with wide distribution, rapid dissemination and high disability rate. However, the molecular mechanism underlying B. burgdorferi mediated neuroborreliosis remains largely unknown. Here, the frontal cortex from rhesus brains was incubated with B. burgdorferi, and proteomics profiling was evaluated by isobaric tag for relative and absolute quantitation. Proteins were identified and quantified, and differentially expressed proteins (DEPs) were isolated by comparing co‐cultured samples and control samples. A total of 43, 164 and 368 DEPs were significantly altered after 6, 12 and 24 h treatment with B. burgdorferi respectively. Gene ontology and KEGG pathway analyses revealed that chemokine biological process was significantly enriched. Two genes in chemokine pathway including GRB2 and ROCK2 were significantly up‐regulated after B. burgdorferi co‐culturing. By in vitro assay, we confirmed that the expression of GRB2 and ROCK2 was increased after B. burgdorferi infection. In conclusion, our study revealed the involvement of chemokine pathway in the pathogenesis of LNB. GRB2 and ROCK2 may be novel biomarkers and therapeutic targets for LNB. [ABSTRACT FROM AUTHOR]

In the tumor microenvironment, inflammation and necrosis cause the accumulations of ATP extracellularly, and high concentrations of ATP can activate P2X7 receptors (P2X7R), which leads to the influx of Na+, K+, or Ca2+ into cells and trigger the downstream signaling pathways. P2X7R is a relatively unique ligand‐gated ion channel, which is over‐expressed in most tumor cells. The activated P2X7R facilitates the tumor growth, invasion, and metastasis. Inhibition of the P2X7R activation can be applied as a potential anti‐tumor therapy strategy. There are currently no anti‐tumor agents against P2X7R, though several P2X7R antagonists for indications such as anti‐inflammatory and anti‐depression were reported. In this study, we combined homology modeling (HM), virtual screening, and EB intake assay to characterize the structural features of P2X7R and identify several novel antagonists, which were chemically different from any other known P2X7R antagonists. The identified antagonists could effectively prevent the pore opening of P2X7R with IC50 values ranging from 29.14 to 35.34 μM. HM model showed the area between ATP‐binding pocket, and allosteric sides were hydrophobic and suitable for small molecule interaction. Molecular docking indicated a universal binding mode, of which residues R294 and K311 were used as hydrogen bond donors to participate in antagonist interactions. The binding mode can potentially be utilized for inhibitor optimization for increased affinity, and the identified antagonists can be further tested for anti‐cancer activity or may serve as chemical agents to study P2X7R related functions. [ABSTRACT FROM AUTHOR]

A pedestrian‐target detection method based on multiscale convolution features is proposed to solve the problem of the existing target detection algorithms based on convolutional neural networks that cannot effectively adapt to the target scale change, its deformation, and the complex environment. This article analyzes the characteristics of small target, establishes the a three‐layer pyramid network structure based on horizontal connection fusion, and makes full use of shallow convolution features with lower semantics to improve the accuracy of small target detection; From the angle of the cross ratio, quantitative analysis is made on the effect of eliminating redundant bounding box by nonmaximum suppression based on center point when the window with the cross ratio is less than 0.7, solves the problem of missing detection of overlap and small target, and improves the target detection accuracy and the generalization ability of the target detection model. Through the experimental results on VOC2007 and VOC2012 public data sets, the proposed method of this article has higher detection accuracy and stability for small and incomplete targets, multiscale target detection, and target classification under the complex environment. [ABSTRACT FROM AUTHOR]

Background and purpose: Buprenorphine displays attributes of opioids, but also some features distinct from them. We examined spinal and supraspinal signal transduction of buprenorphine-induced anti-nociception in mice compared with morphine and fentanyl. Experimental approach: The opioid receptor antagonist naloxone, Pertussis toxin (PTX), Gz protein antisense and nociceptin/orphanin-FQ receptor agonist nociceptin, and antagonist, JTC-801, were injected supraspinally (intracerebroventricular) and spinally (intrathecal). Also the cell-permeable Ser/Thr protein phosphatase inhibitor okadaic acid was given supraspinally. Key results: Spinal naloxone (20 µg) or PTX (1 µg) attenuated morphine, fentanyl and buprenorphine (s.c.) anti-nociception. Supraspinal naloxone or PTX attenuated morphine and fentanyl, but not buprenorphine anti-nociception. Spinal Gz protein antisense did not alter buprenorphine, morphine or fentanyl anti-nociception and supraspinal Gz-antisense did not alter morphine or fentanyl anti-nociception. However, supraspinal Gz-antisense (not random sense) reduced buprenorphine anti-nociception. Peripheral JTC-801 (1 mg·kg−1, i.p.) enhanced the ascending (3 mg·kg−1) and descending (30 mg·kg−1) portions of buprenorphine's dose–response curve, but only spinal, not supraspinal, nociceptin (10 nmol·L−1) enhanced buprenorphine anti-nociception. Intracereboventricular okadaic acid (0.001–10 pg) produced a biphasic low-dose attenuation, high-dose enhancement of buprenorphine(3 or 30 mg·kg−1, s.c.) anti-nociception, but did not affect morphine or fentanyl anti-nociception. Conclusions and implications: Buprenorphine has an opioid component to its supraspinal mechanism of analgesic action. Our present results reveal an additional supraspinal component insensitive to naloxone, PTX and nociceptin/orphanin-FQ, but involving Gz protein and Ser/Thr protein phosphatase. These data might help explain the unique preclinical and clinical profiles of buprenorphine. [ABSTRACT FROM AUTHOR]

Agmatine blocks morphine physical dependence in mammals, but its effects on withdrawal signs caused by other abused drugs have been less studied. One of the reasons is that withdrawal to some of these drugs is difficult to quantify in mammals. An alternative to mammals is planarians, a type of flatworm. Planarians possess mammalian-like neurotransmitters and display withdrawal from amphetamines, benzodiazepines, cannabinoids, cocaine, and opioids. The withdrawal is manifested as a reduction in locomotor behavior following discontinuation of drug exposure. In the present study, our goal was to identify agmatine in planarians and to determine if planarians exposed to agmatine display withdrawal to methamphetamine, a cannabinoid receptor agonist (WIN 55,212-2), or a κ-opioid receptor agonist (U-50,488H). Neurochemical experiments revealed that the concentration of agmatine in planarians was 185 ± 33.7 pmol per mg of planarian weight (dry weight). In behavioral experiments, withdrawal (i.e., reduced locomotor activity) was observed when planarians exposed to each drug (10 μM) for 60 min were placed into water. The withdrawal was attenuated when methamphetamine- or U-50,488H-exposed planarians were tested in agmatine (100 μM). Withdrawal was inhibited similarly when planarians coexposed to agmatine (100 μM) plus methamphetamine (10 μM), WIN 55,212-2 (10 μM), or U-50,488H (10 μM) were tested in water. Arginine, the metabolic precursor to agmatine, was ineffective. Our results identify endogenous agmatine in planarians and demonstrate that agmatine exposure blocks withdrawal to three different drugs in planarians. This suggests that a change in agmatine signaling is a common mechanism in the withdrawal caused by these drugs, at least in planarians. Synapse 62:927-934, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify key candidate genes in prostate cancer. The gene expression profiles of GSE32448, GSE45016, GSE46602 and GSE104749 were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) between prostate cancer and normal samples were identified by R language. The gene ontology functional and pathway enrichment analyses of DEGs were performed by the Database for Annotation, Visualization and Integrated Discovery software followed by the construction of protein–protein interaction network. Hub gene identification was performed by the plug‐in cytoHubba in Cytoscape software. The 217 DEGs were significantly enriched in biological processes including epithelial cell differentiation, response to estradiol and several pathways, mainly associated with protein digestion and absorption pathway in prostate cancer. Epithelial cell adhesion molecule, twist family basic helix–loop–helix transcription factor 1, CD38 molecule and vascular endothelial growth factor A were identified as hub genes. The expression levels of hub genes were consistent with data obtained in The Cancer Genome Atlas for prostate adenocarcinoma. These hub genes may be used as potential targets for prostate cancer diagnosis and treatment. [ABSTRACT FROM AUTHOR]

In the title compound, C(11)H(14)N(4)O(4)·C(2)HCl(3)O(2), the dioxolane ring adopts an envelope conformation. Doxophylline [7-(1,3-dioxolan-2-yl-meth-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione] and trichloro-acetic acid mol-ecules are linked by O-H⋯N and C-H⋯O hydrogen bonds.